The overall objective of this project is to study the role of human natural killer (NK) cells in the regulation of hematopoiesis in physiological and pathological conditions. The underlying hypothesis of this proposal is that NK cells are engaged in the regulation of reactions against self to ensure homeostasis. Rejection of bone marrow graft and some pathological states of bone marrow failure, in which the role of NK cells was demonstrated, would be a consequence of an enhancement or pathological alteration of this physiological regulatory mechanism. The NK-cell-mediated natural resistance to leukemia-lymphomas is probably another manifestation, in pathological conditions, of the hemostatic function of NK cells. Human NK cells inhibit proliferation-differentiation of human bone marrow hematopoietic precursor cells in vitro. This effect is mediated, in part or completely, by release of a soluble colony-inhibiting activity (NK-CIA), probably identical to the NK-derived cytotoxic factor (NKCF) released by NKC cells upon interaction with target cells. The mechanism by which NK cells and NK-CIA suppress hematopoiesis will be characterized. The long range objective is to apply the knowledge acquired from these studies to analyze the possible role of NK cells in patients with transient or severe bone marrow failure and in patients with leukemia-lymphomas. (SR)